CHES1 modulated tumorigenesis and senescence of pancreas cancer cells through repressing AKR1B10.

Pancreatic ductal adenocarcinoma (PDAC), is characteristic by a heterogeneous tumor microenvironment and gene mutations, conveys a dismal prognosis and low response to chemotherapy and immunotherapy. Here, we found that checkpoint suppressor 1 (CHES1) served as a tumor repressor in PDAC and was associated with patient prognosis. Functional experiments indicated that CHES1 suppressed the proliferation and invasion of PDAC by modulating cellular senescence. To further identify the downstream factor of CHES1 in PDAC, label-free quantitative proteomics analysis was conducted, which showed that the oncogenic Aldo-keto reductase 1B10 (AKR1B10) was transcriptionally repressed by CHES1 in PDAC. And AKR1B10 facilitated the malignant activity and repressed senescent phenotype of PDAC cells. Moreover, pharmaceutical inhibition of AKR1B10 with Oleanolic acid (OA) significantly induced tumor regression and sensitized PDAC cells to gemcitabine, and this combined therapy did not cause obvious side effects. Rescued experiments revealed that CHES1 regulated the tumorigenesis and gemcitabine sensitivity through AKR1B10-mediated senescence in PDAC. In summary, this study revealed that the CHES1/AKR1B10 axis modulated the progression and cellular senescence in PDAC, which might provide revenues for drug-targeting and senescence-inducing therapies for PDAC.

Experimental study on the microwave radiation disinfection of E. coli on SiC composite filter.

Filter is an important component in the air-conditioning system. The airborne microorganisms can be intercepted and further multiply on the filter, which might cause a secondary pollution. The present work proposed a SiC composite filter (SCF), namely combining the filter with the absorbing material SiC. The disinfection efficiency (η) and mechanism of the microwave radiation method (MRM) on E. coli and S. aureus attached to the SCF were experimentally explored. The impacts of the microwave power (P) and disinfection time (t) on η were investigated. The results show that the SCF can be heated well by the microwave, but the normal filter (NF) cannot. The MRM can effectively and rapidly disinfect bacteria on the SCF at a sufficiently high P and an appropriate t. Generally, η increases with P and t. Under a specific P, η can be only increased with t at a certain range and a peak η might be reached. When this peak is achieved, η will not be further increased with t. The disinfection by the MRM is attributed to the thermal and non-thermal effects. Specially, at P = 600 W and t = 10 min, the non-thermal effect contributes about 89.6% to the disinfection of the E. coli and about 43.1% to the S. aureus. A universal relationship between η and temperature is given for E. coli and S. aureus to predict η at various P and t. Finally, the effective temperatures required by the MRM to satisfactorily disinfect bacteria on the SCF are identified, i.e., about 41 °C for E. coli and 71 °C for S. aureus.

Acetylation of Checkpoint suppressor 1 enhances its stability and promotes the progression of triple-negative breast cancer.

Checkpoint suppressor 1 (CHES1), a transcriptional regulator, had been dysregulated in many types of malignancies including breast cancer, and its expression level is strongly associated with progression and prognosis of patients. However, the underlying regulatory mechanisms of CHES1 expression in the breast cancer and the effects of post-translational modifications (PTMs) on its functional performance remain to be fully investigated. Herein, we found that CHES1 had a high abundance in triple-negative breast cancer (TNBC) and its expression was tightly associated with malignant phenotype and poor outcomes of patients. Furthermore, we confirmed that CHES1 was an acetylated protein and its dynamic modification was mediated by p300 and HDAC1, and CHES1 acetylation enhanced its stability via decreasing its ubiquitination and degradation, which resulted in the high abundance of CHES1 in TNBC. RNA-seq and functional study revealed that CHES1 facilitated the activation of oncogenic genes and pathways leading to proliferation and metastasis of TNBC. Taken together, this research established a novel regulatory role of acetylation on the stability and activity of CHES1. The results demonstrate the significance of CHES1 acetylation and underlying mechanisms in the progression of TNBC, offering new potential candidate for molecular-targeted therapy in breast cancer.

NIR-II Fluorescence Imaging-Guided Oxygen Self-Sufficient Nano-Platform for Precise Enhanced Photodynamic Therapy.

Tumor hypoxia and systemic toxicity seriously affect the efficacy of photodynamic therapy (PDT) and are considered as the "Achilles' heel" of PDT. Herein, to combat such limitations, an intelligent orthogonal emissions LDNP@SiO2 -CaO2 and folic acid-polyethylene glycol-Ce6 nanodrug is rationally designed and fabricated not only for relieving the hypoxic tumor microenvironment (TME) to enhance PDT efficacy, but also for determining the optimal triggering time through second near-infrared (NIR-II) fluorescence imaging. The designed nanodrug continuously releases a large amount of O2 , H2 O2 , and Ca2+ ions when exposed to the acidic TME. Meanwhile, under downshifting NIR-II bioimaging guidance, chlorine e6 (Ce6) consumes oxygen to produce 1 O2 upon excitation of upconversion photon. Moreover, cytotoxic reactive oxygen species (ROS) and calcium overload can induce mitochondria injury and thus enhance the oxidative stress in tumor cells. As a result, the NIR-II bioimaging guided TME-responsive oxygen self-sufficient PDT nanosystem presents enhanced anti-tumor efficacy without obvious systemic toxicity. Thus, the fabricated nanodrug offers great potential for designing an accurate cancer theranostic system.

Estrogen-Related Receptor α: A Significant Regulator and Promising Target in Bone Homeostasis and Bone Metastasis.

Bone homeostasis is maintained with the balance between bone formation and bone resorption, which is involved in the functional performance of osteoblast and osteoclast. Disruption of this equilibrium usually causes bone disorders including osteoporosis, osteoarthritis, and osteosclerosis. In addition, aberrant activity of bone also contributes to the bone metastasis that frequently occurs in the late stage of aggressive cancers. Orphan nuclear receptor estrogen-related receptor (ERRα) has been demonstrated to control the bone cell fate and the progression of tumor cells in bone through crosstalk with various molecules and signaling pathways. However, the defined function of this receptor in bone is inconsistent and controversial. Therefore, we summarized the latest research and conducted an overview to reveal the regulatory effect of ERRα on bone homeostasis and bone metastasis, this review may broaden the present understanding of the cellular and molecular model of ERRα and highlight its potential implication in clinical therapy.

Amorphous ferric oxide-coating selenium core-shell nanoparticles: a self-preservation Pt(IV) platform for multi-modal cancer therapies through hydrogen peroxide depletion-mediated anti-angiogenesis, apoptosis and ferroptosis.

A self-preservation Pt(IV) nanoplatform, amorphous ferric oxide-coating selenium core-shell nanoparticles (iAIO@NSe-Pt), was developed for H2O2 depletion-mediated tumor anti-angiogenesis, apoptosis, and ferroptosis. Upon entry into the blood, the ferric oxide shell effectively blocked the contact Pt(IV) prodrug with reduced molecules, then avoided the inactivation of the Pt(IV) prodrug and increased its accumulation in the tumor. After entering cancer cells, iAIO@NSe-Pt caused a series of cascade reactions: (1) AIO on the surface of iAIO@NSe-Pt quickly dissolved, released an abundance of Fe(II) because of the weakly acidic tumor microenvironment, and then catalyzed cellular H2O2 into highly toxic ˙OH, resulting in cellular H2O2 deficiency and cell ferroptosis. (2) The platinum(IV) prodrugs were exposed and quickly reduced to highly toxic Pt(II) by depleting GSH. This process inactivated GPX4, promoted ROS accumulation, and further accelerated ferroptosis. In addition, the generated Pt(II) quickly inhibited DNA replication, achieving effective apoptotic cell death. Meanwhile, Pt(II) inactivated SOD1, which blocked the synthesis of cellular H2O2 and accelerated ROS (superoxide anion radical) accumulation. (3) The deficiency of cellular H2O2 significantly inhibited the expression of vascular endothelial growth factor-A (VEGF-A), blocking tumor angiogenesis and then improving the anticancer effect. (4) After such a cascade reaction, the exposed NSe successively disrupted mitochondrial respiration and inhibited cancer angiogenesis, further inducing cancer cell death. Collectively, our functional and mechanical investigation suggested that iAIO@NSe-Pt exhibits excellent tumor targeting, biocompatibility and anti-tumor efficiency in vitro and in vivo, and provides a novel example of a self-preservation Pt(IV) nanoplatform for H2O2 depletion-mediated tumor anti-angiogenesis, apoptosis, and ferroptosis, showing great promise for future clinical use.

PDGFB targeting biodegradable FePt alloy assembly for MRI guided starvation-enhancing chemodynamic therapy of cancer.

The application of chemodynamic therapy (CDT) for cancer is a serious challenge owing to the low efficiency of the Fenton catalyst and insufficient H2O2 expression in cells. Herein, we fabricated a PDGFB targeting, biodegradable FePt alloy assembly for magnetic resonance imaging (MRI)-guided chemotherapy and starving-enhanced chemodynamic therapy for cancer using PDGFB targeting, pH-sensitive liposome-coated FePt alloys, and GOx (pLFePt-GOx). We found that the Fenton-catalytic activity of FePt alloys was far stronger than that of traditional ultrasmall iron oxide nanoparticle (UION). Upon entry into cancer cells, pLFePt-GOx nanoliposomes degraded into many tiny FePt alloys and released GOx owing to the weakly acidic nature of the tumor microenvironment (TME). The released GOx-mediated glucose consumption not only caused a starvation status but also increased the level of cellular H2O2 and acidity, promoting Fenton reaction by FePt alloys and resulting in an increase in reactive oxygen species (ROS) accumulation in cells, which ultimately realized starving-enhanced chemodynamic process for killing tumor cells. The anticancer mechanism of pLFePt-GOx involved ROS-mediated apoptosis and ferroptosis, and glucose depletion-mediated starvation death. In the in vivo assay, the systemic delivery of pLFePt-GOx showed excellent antitumor activity with low biological toxicity and significantly enhanced T2-weighted magnetic resonance imaging (MRI) signal of the tumor, indicating that pLFePt-GOx can serve as a highly efficient theranostic tool for cancer. This work thus describes an effective, novel multi-modal cancer theranostic system.

SARS-CoV-2-specific antibody response characteristics in COVID-19 patients of different ages.

Age has been found to be one of the main risk factors for the severity and outcome of COVID-19. However, differences in SARS-CoV-2 specific antibody responses among COVID-19 patients of different age groups remain largely unknown. In this study, we analyzed the IgG/IgM responses to 21 SARS-CoV-2 proteins and 197 peptides that fully cover the spike protein against 731 sera collected from 731 COVID-19 patients aged from 1 to We show that there is no overall difference in SARS-CoV-2 antibody responses in COVID-19 patients in the 4 age groups. By antibody response landscape maps, we find that the IgG response profiles of SARS-CoV-2 proteins are positively correlated with age. The S protein linear epitope map shows that the immunogenicity of the S-protein peptides is related to peptide sequence, disease severity and age of the COVID-19 patients. Furthermore, the enrichment analysis indicates that low S1 IgG responses are enriched in patients aged <50 and high S1 IgG responses are enriched in mild COVID-19 patients aged >60. In addition, high responses of non-structural/accessory proteins are enriched in severe COVID-19 patients aged >70. These results suggest the distinct immune response of IgG/IgM to each SARS-CoV-2 protein in patients of different age, which may facilitate a deeper understanding of the immune responses in COVID-19 patients.

CuO dot-decorated Cu@Gd2O3 core-shell hierarchical structure for Cu(i) self-supplying chemodynamic therapy in combination with MRI-guided photothermal synergistic therapy.

Theoretically, the Fenton catalytic efficiency of the Cu-based nanoplatform is approximately 160 times that of traditional Fe-based agents. However, the coordination interaction between Cu(ii) and intracellular GSH significantly inhibits the high catalytic activity of Cu(i) generation, dramatically decreasing the Fenton-like catalytic efficiency. Herein, we designed a completely new and highly efficient hierarchical structural nanoplatform to enhance the mimic-peroxidase activity through utilizing comproportionation between CuO and elemental Cu core to self-supply Cu(i). The catalytic rate of this nanoplatform was approximately 55-fold that of traditional Fe-based agents. In a cell assay, this nanoplatform could function as an antagonist of GPX4 and agonist of SOD-1, resulting in intracellular ROS and H2O2 accumulation. Next, the accumulated H2O2 could be quickly catalyzed to highly toxic ˙OH by self-supplying Cu(i), causing strong oxidative stress damage to mitochondria and cell membranes. Under 808 nm laser irradiation, this nanoplatform exhibited a stronger inhibition of tumor growth, and effectively overcame the tumor resistance and recurrence. In addition, this hierarchical structure significantly promoted the interaction between water molecules and gadolinium centers, making TRF-mCuGd possess an ultrahigh T1 MRI contrast performance, and hence, more pathological information of the tumor could be achieved. Overall, this work provides a promising pattern for the design and development of cancer theranostics.

A nanoselenium-coating biomimetic cytomembrane nanoplatform for mitochondrial targeted chemotherapy- and chemodynamic therapy through manganese and doxorubicin codelivery.

The cell membrane is widely considered as a promising delivery nanocarrier due to its excellent properties. In this study, self-assembled Pseudomonas geniculate cell membranes were prepared with high yield as drug nanocarriers, and named BMMPs. BMMPs showed excellent biosafety, and could be more efficiently internalized by cancer cells than traditional red cell membrane nanocarriers, indicating that BMMPs could deliver more drug into cancer cells. Subsequently, the BMMPs were coated with nanoselenium (Se), and subsequently loaded with Mn2+ ions and doxorubicin (DOX) to fabricate a functional nanoplatform (BMMP-Mn2+/Se/DOX). Notably, in this nanoplatform, Se nanoparticles activated superoxide dismutase-1 (SOD-1) expression and subsequently up-regulated downstream H2O2 levels. Next, the released Mn2+ ions catalyzed H2O2 to highly toxic hydroxyl radicals (·OH), inducing mitochondrial damage. In addition, the BMMP-Mn2+/Se nanoplatform inhibited glutathione peroxidase 4 (GPX4) expression and further accelerated intracellular reactive oxygen species (ROS) generation. Notably, the BMMP-Mn2+/Se/DOX nanoplatform exhibited increased effectiveness in inducing cancer cell death through mitochondrial and nuclear targeting dual-mode therapeutic pathways and showed negligible toxicity to normal organs. Therefore, this nanoplatform may represent a promising drug delivery system for achieving a safe, effective, and accurate cancer therapeutic plan.

The binding epitope of sintilimab on PD-1 revealed by AbMap.

PD-1 plays an important role as an immune checkpoint. Sintilimab is a newly approved PD-1 antibody for cancer immunotherapy with an unknown binding epitope on PD-1. In this study, to elucidate the molecular mechanism by which sintilimab blocks PD-1 activation, we applied Antibody binding epitope Mapping (AbMap) to identify the binding epitope of sintilimab. An epitope was successfully identified, i.e. SLAPKA, aa 127-132. By constructing a series of point mutations, the dominant residues S127, L128, A129, P130, and A132 of PD-1 were further validated by western blot analysis, biolayer interferometry, and flow cytometry. Structural analysis showed that the epitope is partially within the binding interface of PD-1 and PD-L1, and this epitope also partially overlaps with that of nivolumab and pembrolizumab. These results demonstrate that sintilimab can attenuate PD-1 activation by directly competing with the interaction between PD-1 and PD-L1 through binding with the key residues of the FG loop on PD-1. This study also demonstrates the high efficiency and accuracy of AbMap for determining the binding epitope of therapeutic antibodies.

Systematic evaluation of IgG responses to SARS-CoV-2 spike protein-derived peptides for monitoring COVID-19 patients.

Serological tests play an essential role in monitoring and combating the COVID-19 pandemic. Recombinant spike protein (S protein), especially the S1 protein, is one of the major reagents used for serological tests. However, the high cost of S protein production and possible cross-reactivity with other human coronaviruses pose unavoidable challenges. By taking advantage of a peptide microarray with full spike protein coverage, we analyzed 2,434 sera from 858 COVID-19 patients, 63 asymptomatic patients and 610 controls collected from multiple clinical centers. Based on the results, we identified several S protein-derived 12-mer peptides that have high diagnostic performance. In particular, for monitoring the IgG response, one peptide (aa 1148-1159 or S2-78) exhibited a sensitivity (95.5%, 95% CI 93.7-96.9%) and specificity (96.7%, 95% CI 94.8-98.0%) comparable to those of the S1 protein for the detection of both symptomatic and asymptomatic COVID-19 cases. Furthermore, the diagnostic performance of the S2-78 (aa 1148-1159) IgG was successfully validated by ELISA in an independent sample cohort. A panel of four peptides, S1-93 (aa 553-564), S1-97 (aa 577-588), S1-101 (aa 601-612) and S1-105 (aa 625-636), that likely will avoid potential cross-reactivity with sera from patients infected by other coronaviruses was constructed. The peptides identified in this study may be applied independently or in combination with the S1 protein for accurate, affordable, and accessible COVID-19 diagnosis.

A Meta-Analysis on the Association Between TNFSF4 Polymorphisms (rs3861950 T > C and rs1234313 A > G) and Susceptibility to Coronary Artery Disease.

Background: Coronary artery disease (CAD) remains the leading cause of mortality worldwide, and its susceptibility is closely associated with genetic modifications. The association between inflammation and CAD has been investigated in detail. This meta-analysis was conducted based on the PRISMA guidelines to evaluate the association between the tumor necrosis factor superfamily member 4 (TNFSF4) gene polymorphisms (rs3861950 T > C and rs1234313 A > G) and the risk of CAD. Methods: The selected criteria included 11 eligible articles containing 18 studies (nine studies included 7,395 cases and 5,296 controls for rs3861950 and nine studies with 6,951 cases and 4,959 controls for rs1234313). Correlations between the two polymorphisms and CAD were estimated by pooling the odds ratios (ORs) with 95% confidence interval (95% CI) in allelic, dominant, recessive, heterozygous, and homozygous models. Results: The pooled analyses demonstrated that the rs3861950 T > C polymorphism was significantly associated with an increased risk of CAD in the Asian population in the allelic model, dominant model, and homozygous model. Furthermore, subgroup analysis based on disease type showed that TNFSF4 rs3861950 T > C had a robust correlation with increased risk of cerebral infarction (CI) in the allelic model, dominant model, heterozygous model, and homozygous model. However, the rs1234313 A > G polymorphism mostly tended to decrease the risk of CAD in the Asian and Caucasian populations in the allelic and dominant model. This single nucleotide polymorphism (SNP) had a close relation to myocardial infarction (MI) susceptibility in the allelic model, dominant model, and heterozygous model. Conclusion: This meta-analysis identified two novel SNPs in TNFSF4 significantly associated with CAD susceptibility.

Oxygen Vacancy Defect-Induced Activity Enhancement of Gd Doping Magnetic Nanocluster for Oxygen Supplying Cancer Theranostics.

This work finds that Fe3O4 nanoclusters can rearrange by Gd doping and then self-assemble to a hollow magnetic nanocluster (HMNC), providing larger magnetic moments to obtain an excellent MRI capability and increasing the number of oxygen vacancies in HMNC. The hollow structure makes platinum(IV) prodrugs effectively load into HMNC. Second, plenty of oxygen vacancy defects can capture oxygen molecules, enhance the catalytic activity of HMNC, and then promote intracellular ROS generation. On the basis of this, a targeting iRGD-labeled HMNC nanosystem (iHMNCPt-O2) is developed through loading oxygen molecules and platinum(IV) prodrugs for chemo- and chemodynamic therapy of cancer. This nanosystem shows an excellent response ability to weak acid and GSH, which can cause a series of cascade reactions in a cell. These cascade reactions are dramatically enhanced at the intracellular ROS level, cause mitochondria and DNA damage, and then induce cancer cell death. Besides, systemic delivery of iHMNCPt-O2 significantly enhanced the MRI contrast signal of tumors and improved the quality of MR images, accurately diagnosing tumors. Therefore, this work provides a novel method for accelerating the Fenton-like reaction and enhancing the MRI capability and fabricates a promising "all-in-one" system to overwhelm the problems of cancer theranostic.

Identification of Serum Biomarkers for Systemic Lupus Erythematosus Using a Library of Phage Displayed Random Peptides and Deep Sequencing.

Systemic lupus erythematosus (SLE) is one of the most serious autoimmune diseases, characterized by highly diverse clinical manifestations. A biomarker is still needed for accurate diagnostics. SLE serum autoantibodies were discovered and validated using serum samples from independent sample cohorts encompassing 306 participants divided into three groups, i.e. healthy, SLE patients, and other autoimmune-related diseases. To discover biomarkers for SLE, a phage displayed random peptide library (Ph.D. 12) and deep sequencing were applied to screen specific autoantibodies in a total of 100 serum samples from 50 SLE patients and 50 healthy controls. A statistical analysis protocol was set up for the identification of peptides as potential biomarkers. For validation, 10 peptides were analyzed using enzyme-linked immunosorbent assays (ELISA). As a result, four peptides (SLE2018Val001, SLE2018Val002, SLE2018Val006, and SLE2018Val008) were discovered with high diagnostic power to differentiate SLE patients from healthy controls. Among them, two peptides, i.e. SLE2018Val001 and SLE2018Val002, were confirmed between SLE with other autoimmune patients. The procedure we established could be easily adopted for the identification of autoantibodies as biomarkers for many other diseases.

Checkpoint suppressor 1 suppresses transcriptional activity of ERα and breast cancer cell proliferation via deacetylase SIRT1.

Breast cancer is a highly heterogeneous carcinoma in women worldwide, but the underlying mechanisms that account for breast cancer initiation and development have not been fully established. Mounting evidence indicates that Checkpoint suppressor 1 (CHES1) is tightly associated with tumorigenesis and prognosis in many types of cancer. However, the definitive function of CHES1 in breast cancer remains to be explored. Here we showed that CHES1 had a physical interaction with estrogen receptor-α (ERα) and repressed the transactivation of ERα in breast cancer cells. Mechanistically, the interaction between CHES1 and ERα enhanced the recruitment of nicotinamide adenine dinucleotide (NAD+) deacetylase Sirtuin 1 (SIRT1), and it further induced SIRT1-mediated ERα deacetylation and repression on the promoter-binding enrichment of ERα. In addition, we also found that the expression of CHES1 was repressed by estrogen-ERα signaling and the expression level of CHES1 was significantly downregulated in ERα-positive breast cancer. The detailed mechanism was that ERα may directly bind to CHES1 potential promoter via recognizing the conserved estrogen response element (ERE) motif in response to estrogen stimulation. Functionally, CHES1 inhibited ERα-mediated proliferation and tumorigenesis of breast cancer cells in vivo and in vitro. Totally, these results identified a negative cross-regulatory loop between ERα and CHES1 that was required for growth of breast cancer cells, it might uncover novel insight into molecular mechanism of CHES1 involved in breast cancer and provide new avenues for molecular-targeted therapy in hormone-regulated breast cancer.

Identification of Serine 119 as an Effective Inhibitor Binding Site of M. tuberculosis Ubiquitin-like Protein Ligase PafA Using Purified Proteins and M. smegmatis.

Owing to the spread of multidrug resistance (MDR) and extensive drug resistance (XDR), there is a pressing need to identify potential targets for the development of more-effective anti-M. tuberculosis (Mtb) drugs. PafA, as the sole Prokaryotic Ubiquitin-like Protein ligase in the Pup-proteasome System (PPS) of Mtb, is an attractive drug target. Here, we show that the activity of purified Mtb PafA is significantly inhibited upon the association of AEBSF (4-(2-aminoethyl) benzenesulfonyl fluoride) to PafA residue Serine 119 (S119). Mutation of S119 to amino acids that resemble AEBSF has similar inhibitory effects on the activity of purified Mtb PafA. Structural analysis reveals that although S119 is distant from the PafA catalytic site, it is located at a critical position in the groove where PafA binds the C-terminal region of Pup. Phenotypic studies demonstrate that S119 plays critical roles in the function of Mtb PafA when tested in M. smegmatis. Our study suggests that targeting S119 is a promising direction for developing an inhibitor of M. tuberculosis PafA.

α-catenin SUMOylation increases IκBα stability and inhibits breast cancer progression.

α-catenin has been demonstrated to suppress several different types of cancers. Here we demonstrate that α-catenin is modified by SUMO protein, which covalently binds α-catenin at the carboxy terminus at lysine 870. Substitution of lysine 870 with arginine completely abolishes α-catenin SUMOylation. This modification can be removed by SENP1. However, α-catenin SUMOylation does not affect its stability and subcellular localization. In addition, we observed that the SUMOylation-deficient α-catenin mutant has a reduced interaction with IκBα which prevents subsequent ubiquitination of IκBα, and therefore a reduced suppression of expression of the NF-κB target genes TNF-α, IL-8, VEGF, and uPA. In addition, the α-catenin SUMOylation mutant shows impaired suppression of tumor growth. These results demonstrate that SUMOylation at lysine 870 of α-catenin plays a key role in the suppression of the NF-κB pathway, which inhibits breast cancer tumor growth and migration.

U-box ubiquitin ligase PPIL2 suppresses breast cancer invasion and metastasis by altering cell morphology and promoting SNAI1 ubiquitination and degradation.

Metastasis is the leading cause of breast cancer fatalities. To develop new therapeutic strategies, the mechanisms underlying breast cancer invasion and metastasis need to be further investigated. Peptidylprolyl isomerase (cyclophilin)-like 2 (PPIL2) is a U-box-type E3 ubiquitin ligase belonging to the cyclophilin family. Proteins within this family are the major cytosolic binding proteins of the immunosuppressant drug cyclosporine A (CsA). Although PPIL2 has been reported to potentially be involved in cell migration, its role in breast cancer is still unclear. Herein, we demonstrate that PPIL2 suppressed metastasis in a breast cancer model by altering cell morphology and suppressing the epithelial-mesenchymal transition (EMT) process. Moreover, elevated PPIL2 inhibited EMT and breast cancer invasion by interacting with the classical EMT transcription factor, SNAI1, to enhance its ubiquitin-dependent degradation. Furthermore, PPIL2 protein level and stability was upregulated after CsA treatment, indicating that PPIL2 might be involved in CsA-mediated repression of EMT in breast cancer. Analysis of tissue samples taken from breast cancer patients showed a significant correlation between the expression of PPIL2 and the degree of cancer invasion and metastasis. In summary, these results would shed light on a potential clinical use of CsA in breast cancer patients.

Krüppel-like factor 9 down-regulates matrix metalloproteinase 9 transcription and suppresses human breast cancer invasion.

Krüppel-like factor 9 (KLF9) plays critical roles in several types of tumor. However, the biological functions and the underlying mechanisms of KLF9 in breast cancer metastasis are still unknown. Here, we found the expression of KLF9 was significantly down-regulated in breast cancer and was inversely correlated with the expression of matrix metalloproteinase 9 (MMP9) in breast cancer patients. Functionally, KLF9 transcriptionally down-regulated MMP9 expression and inhibited the metastasis of breast cancer cells. Mechanistically, KLF9 repressed human MMP9 promoter activity by binding to the CACCC motif and interacting with NF-κB p50/p65, which interacted with the NF-κB response element of the MMP9 promoter, leading to decreased expression of MMP9. In the context of breast cancer, KLF9 promoted the accumulation of HDAC1, thereby decreasing the acetylation of the KLF9-binding site on the MMP9 promoter, and this might be the molecular basis of KLF9-mediated inhibition of MMP9 transcription. In addition to MMP9, KLF9 also down-regulated several other NF-κB targets, such as TNF-α, VEGFA and uPA in breast cancer cells. Taken together, these results uncovered a new mechanism by which KLF9 could down-regulate MMP9 expression to inhibit breast cancer metastasis.